rs869025217

Variant names:

• chr3-184170318-G-A
• rs869025217
• NM_004423.4:c.1715-1G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-184170318-G-A
• chr3-184170318-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004423.4(DVL3):​c.1715-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DVL3 NM_004423.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 3.69
• Publications: 1 publications found

Genes affected

DVL3 (HGNC:3087): (dishevelled segment polarity protein 3) This gene is a member of a multi-gene family which shares strong similarity with the Drosophila dishevelled gene, dsh. The Drosophila dishevelled gene encodes a cytoplasmic phosphoprotein that regulates cell proliferation. [provided by RefSeq, Jul 2008]

DVL3 Gene-Disease associations (from GenCC):

• autosomal dominant Robinow syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant Robinow syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.7, offset of 1, new splice context is: ccctgtttgcctcctacaAGcag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-184170318-G-A is Pathogenic according to our data. Variant chr3-184170318-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DVL3	NM_004423.4	c.1715-1G>A		splice_acceptor_variant, intron_variant	Intron 14 of 14	ENST00000313143.9	NP_004414.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DVL3	ENST00000313143.9	c.1715-1G>A		splice_acceptor_variant, intron_variant	Intron 14 of 14	1	NM_004423.4	ENSP00000316054.3
DVL3	ENST00000431765.6	c.1664-1G>A		splice_acceptor_variant, intron_variant	Intron 14 of 14	5		ENSP00000405885.1
DVL3	ENST00000478247.1	n.1715-1G>A		splice_acceptor_variant, intron_variant	Intron 12 of 12	5
DVL3	ENST00000649847.1	n.*645-1G>A		splice_acceptor_variant, intron_variant	Intron 9 of 9			ENSP00000497654.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Robinow syndrome 3 Pathogenic:2

Jul 15, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 supporting, PM1 moderated, PM2 moderated, PM6 moderated -

Apr 04, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal dominant Robinow syndrome 1 Pathogenic:1

Dec 01, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Autosomal dominant Robinow syndrome 2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		3.7
GERP RS		4.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.86		Position offset: 2
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869025217; hg19: chr3-183888106;